The invention relates to methods for making polymorphic Form II of clarithromycin via slurrying polymorphic Form 0 of clarithromycin in water. The invention also relates to methods for making polymorphic Form IV of clarithromycin.
By slurrying in water, clarithromycin Form 0 can be converted to clarithromycin Form II. Under different conditions, a novel polymorphic form of clarithromycin, designated Form IV can be formed. The invention relates to the use of clarithromycin polymorphs so formed in pharmaceutical compositions; and to methods of using them.
6-O-methyl erythromycin A (clarithromycin) is a semisynthetic macrolide antibiotic related to erythromycin A. Clarithromycin exhibits excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria, Mycoplasma, and Chlamydia. It is stable under acidic conditions and is efficacious when administered orally. Clarithromycin is useful therapy for infections of the upper respiratory tract in children and adults. Clarithromycin is stable under acidic conditions and is efficacious when administered orally.
The chemical structure of clarithromycin is: 
Several crystal forms of clarithromycin and/or solvates of clarithromycin, xe2x80x9cForm 0,xe2x80x9d xe2x80x9cForm Ixe2x80x9d, and xe2x80x9cForm IIxe2x80x9d have been identified as indicated in U.S. Pat. No. 5,945,405. The crystal form of clarithromycin is typically identified by the powder x-ray diffraction patterns. Different crystalline forms of clarithromycin may have different thermal stability, cost of preparation, dissolution characteristics and bioavailability.
Various methods of preparing clarithromycin described in the patent literature have been reported to result in different forms of clarithromycin. Purification of crude clarithromycin has been reported to convert one form of clarithromycin to another form. For example, methods in which the compound is purified by recrystallization from ethanol, have been reported to result in the initial formation of Form 0 solvate (see U.S. Pat. No. 5,945,405) or in the initial formation of Form I (See U.S. Pat. No. 5,858,986). The Form 0 solvate may be used as a therapeutic agent, as described in U.S. Pat. No. 5,945,405. The ""405 patent discloses that the Form 0 solvate may be converted to the non-solvated Form I by removing the solvent by drying at a temperature of from about 0xc2x0 C. to about 50xc2x0 C. Another form, Form II, is reported to be relatively thermodynamically stable compared to Form I. The clarithromycin currently marketed in the United States under the trademark Biaxin(copyright) is formulated using Form II.
Several methods of converting clarithromycin Form 0 or Form I to Form II have been described. One such method, as described in U.S. Pat. No. 4,945,405 and U.S. Pat. No. 5,858,986, is to heat Form 0 under vacuum at a temperature of between about 70xc2x0 C. and 110xc2x0 C. According to this patent, the Form 0 solvate first converts to Form I clarithromycin and then to Form II. This method is described in U.S. Pat. No. 4,945,405 and U.S. Pat. No. 5,858,986. However, this vacuum drying step of converting Form 0 to Form II is expensive in both energy and material handling. Clarithromycin Form II has been reported to be formed when Form I is crystallized from various solvents, including ethanol and water (U.S. Pat. No. 5,844,105).
The invention relates to methods for making polymorphic forms of clarithromycin via slurrying clarithromycin Form 0 in water. By slurrying in water, clarithromycin Form 0 can be converted to clarithromycin Form II.
Under different conditions, a novel polymorphic form of clarithromycin, designated Form IV, can be formed. Such conditions for example, include precipitation from aqueous ethanol at neutralization of the salt of clarithromycin with formic acid by sodium hydroxide at low temperature.
The invention relates to the use of clarithromycin polymorphs so formed in pharmaceutical compositions; and to methods of using them.
The present invention relates to a process for converting clarithromycin Form 0 to clarithromycin Form II, which includes slurrying clarithromycin Form 0 in water. The present invention also relates to processes for the preparation of clarithromycin Form II by converting erythromycin A to clarithromycin and thereafter, converting clarithromycin Form 0 to clarithromycin Form II by slurrying.
Additionally, the present invention relates to a novel polymorph of clarithromycin, that is, clarithromycin Form IV, a process for its preparation, pharmaceutical compositions that include Form IV and methods of using Form IV as a therapeutic agent.
Clarithromycin Form IV can be characterized by its powder x-ray diffraction pattern, which exhibits characteristic peaks at 7.6xc2x0xc2x10.2, 8.1xc2x0xc2x10.2, 9.40xc2x0xc2x10.2, 11.0xc2x0xc2x10.2, 12.0xc2x0xc2x10.2, 15.4xc2x0xc2x10.2, 16.5xc2x0xc2x10.2, 18.7xc2x0xc2x10.2, and 19.3xc2x0xc2x10.2.